Toxicity of minoxidil - Comprehensive in silico prediction of main toxicity endpoints: Acute toxicity, irritation of skin and eye, genetic toxicity, health effect, cardiotoxicity and endocrine system disruption.

This article focusses on elucidating the toxicological profile of minoxidil, a widely used pharmacological agent for alopecia, through the application of in silico methods (Percepta ACD/Labs software). This research is driven by the need to understand key toxicological endpoints: acute toxicity, skin and eye irritation, genetic toxicity, cardiotoxicity, disruption of the endocrine system, and estimation of various health effects due to the lack of experimental data for this drug. These parameters are critically evaluated to meet the stringent requirements of the pharmaceutical industry's safety assessments. The results obtained for acute toxicity (LD50 for rats and mouse) indicate that minoxidil exhibits a species-dependent acute toxicity profile e.g. 51 mg/kg bw for intravenous administration in mice. The predicted health effects indicate a 93% risk to the gastrointestinal system, 54% for the kidneys, 52% for the liver, 42% for the blood and lungs, and 39% for the cardiovascular system. The prediction of genotoxicity suggests a moderate probability (48%) of inducing a positive Ames test result. Furthermore, moderate inhibition of the hERG channel indicates potential cardiac risks of Minoxidil. Based on the information obtained, we propose subjecting minoxidil to additional toxicological assessments. The successful adoption of these in silico methodologies aligns with the 3 R s principle (replacement, reduction, and refinement) in the field of modern toxicological studies of minoxidil, all without the use of laboratory animals for the novelty of our toxicity assessment.

Toxicological assessment of minoxidil: A drug with therapeutic potential besides alopecia.

Minoxidil is regularly prescribed for alopecia, and its therapeutic potential has expanded in recent times. However, few studies have been conducted to evaluate its toxicity, and controversial findings regarding its mutagenic activities remain unsolved. This study aimed to access cytotoxic, genotoxic, and mutagenic properties of minoxidil using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, comet assay, and micronucleus test in mouse fibroblast (L929) cells and its point mutation induction potential in the Salmonella/microsome assay. Furthermore, an in vivo toxicity assessment was conducted in Caenorhabditis elegans. Minoxidil showed cytotoxicity at 2.0 mg/mL in MTT assay. Genotoxicity was observed after 3 h treatment in L929 cells using comet assay. No mutagenic effect was observed in both the micronucleus test and the Salmonella/microsome assay. The lethal dose 50 in C. elegans was determined to be 1.75 mg/mL, and a delay in body development was detected at all concentrations. In conclusion, minoxidil induces DNA damage only in early treatment, implying that this DNA damage may be repairable. This observation corroborates the absence of mutagenic activities observed in L929 cells and Salmonella typhimurium strains. However, the toxicity of minoxidil was evident in both C. elegans and L929 cells, underscoring the need for caution in its use.

Comparative effects of finasteride and minoxidil on the male reproductive organs: A systematic review of in vitro and in vivo evidence.

Finasteride and minoxidil are medicaments commonly prescribed for treating benign prostatic hyperplasia (BPA), hypertension, and/or androgenetic alopecia (AGA). The mechanism of action of finasteride is based on the interference in androgenic pathways, which may lead to fertility-related disorders in men. Minoxidil, however, can act in multiple ways, and there is no consensus that its use can adversely affect male fertility. Since finasteride and minoxidil could be risk factors for male fertility, we aimed to compare their impact on the two reproductive organs testis and epididymis of adult murine models, besides testis/epididymis-related cells, and describe the mechanism of action involved. For such, we used the PRISMA guideline. We included 31 original studies from a structured search on PubMed/MEDLINE, Scopus, and Web of Science databases. For in vivo studies, the bias analysis and the quality of the studies were assessed as described by SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation). We concluded that finasteride and minoxidil act as hormone disruptors, causing oxidative stress and morphological changes mainly in the testis. Our results also revealed that finasteride treatment could be more harmful to male reproductive health because it was more associated with reproductive injuries, including damage to the epididymis, erectile dysfunction, decreased libido, and reduced semen volume. Thus, this study contributes to the global understanding of the mechanisms by which medicaments used for alopecia might lead to male reproductive disorders. We hope that our critical analysis expedites clinical research and reduces methodological bias. The registration number on the Prospero platform is CRD42022313347.

The hydroxypropyl-ß-cyclodextrin-minoxidil inclusion complex improves the cardiovascular and proliferative adverse effects of minoxidil in male rats: Implications in the treatment of alopecia.

The efficacy of minoxidil (MXD) ethanolic solutions (1%-5% w/v) in the treatment of androgenetic alopecia is limited by adverse reactions. The toxicological effects of repeated topical applications of escalating dose (0.035%-3.5% w/v) and of single and twice daily doses (3.5% w/v) of a novel hydroxypropyl-ß-cyclodextrin MXD GEL formulation (MXD/HP-ß-CD) and a MXD solution were investigated in male rats. The cardiovascular effects were evaluated by telemetric monitoring of ECG and arterial pressure in free-moving rats. Ultrasonographic evaluation of cardiac morphology and function, and histopathological and biochemical analysis of the tissues, were performed. A pharmacovigilance investigation was undertaken using the EudraVigilance database for the evaluation of the potential cancer-related effects of topical MXD. Following the application of repeated escalating doses of MXD solution, cardiac hypertrophy, hypotension, enhanced serum natriuretic peptides and K+ -ion levels, serum liver biomarkers, and histological lesions including renal cancer were observed. In addition, the administration of a twice daily dose of MXD solution, at SF rat vs human = 311, caused reductions in the systolic, diastolic, and mean blood pressure of the rats (-30.76 ± 3%, -28.84 ± 4%, and -30.66 ± 5%, respectively, vs the baseline; t test P < .05). These effects were not reversible following washout of the MXD solution. Retrospective investigation showed 32 cases of cancer associated with the use of topical MXD in humans. The rats treated with MXD HP-ß-CD were less severely affected. MXD causes proliferative adverse effects. The MXD HP-ß-CD inclusion complex reduces these adverse effects.

Natriuretic Peptides as Cardiovascular Safety Biomarkers in Rats: Comparison With Blood Pressure, Heart Rate, and Heart Weight.

Cardiovascular (CV) toxicity is an important cause of failure during drug development. Blood-based biomarkers can be used to detect CV toxicity during preclinical development and prioritize compounds at lower risk of causing such toxicities. Evidence of myocardial degeneration can be detected by measuring concentrations of biomarkers such as cardiac troponin I and creatine kinase in blood; however, detection of functional changes in the CV system, such as blood pressure, generally requires studies in animals with surgically implanted pressure transducers. This is a significant limitation because sustained changes in blood pressure are often accompanied by changes in heart rate and together can lead to cardiac hypertrophy and myocardial degeneration in animals, and major adverse cardiovascular events (MACE) in humans. Increased concentrations of NPs in blood correlate with higher risk of cardiac mortality, all-cause mortality, and MACE in humans. Their utility as biomarkers of CV function and toxicity in rodents was investigated by exploring the relationships between plasma concentrations of NTproANP and NTproBNP, blood pressure, heart rate, and heart weight in Sprague Dawley rats administered compounds that caused hypotension or hypertension, including nifedipine, fluprostenol, minoxidil, L-NAME, L-thyroxine, or sunitinib for 1-2 weeks. Changes in NTproANP and/or NTproBNP concentrations were inversely correlated with changes in blood pressure. NTproANP and NTproBNP concentrations were inconsistently correlated with relative heart weights. In addition, increased heart rate was associated with increased heart weights. These studies support the use of natriuretic peptides and heart rate to detect changes in blood pressure and cardiac hypertrophy in short-duration rat studies.

Minoxidil topical solution: an unsafe product for children.

Minoxidil hair formulation is commonly used for the treatment of male or female androgenic alopecia. This over-the-counter product is wrongly considered safe. The ingestion of a few milliliters by a child can lead to significant intoxication. We report a case of significant intoxication after the ingestion of topical minoxidil (Alopexy; Pierre Fabre Laboratoires, SA, Switzerland). A 7-year-old girl, who accidentally ingested a teaspoon of minoxidil hair solution, presented to the pediatric emergency department for emesis. At admission, she had a blood pressure of 86/56 mm Hg and a pulse of 149 beats per minute. Hypotension lasted 40 hours with the lowest value 24 hours after ingestion (79/33 mm Hg). She presented electrocardiogram changes (sinus tachycardia and flattening T-waves) but normal cardiac enzymes. Infusion of 20 mL/kg of normal saline fluid had no hemodynamic effect. Her blood pressure normalized on day 2. Minoxidil topical solution is an unsafe product for children. This formulation should be strictly kept out of reach of children and manufacturers should enhance child-resistance security of packaging. The over-the-counter availability must be questioned.

Cardiovascular toxicity of minoxidil in the marmoset.

The aim of the experiments was to assess the toxicity of minoxidil, a potent vasodilator, in marmosets. The animals were treated either at escalating doses from 2 to 40 mg/kg, escalating doses from 40 to 200 mg/kg or single doses of 150 mg/kg or 200 mg/kg. ECG recording and echocardiographic examination were conducted before and 1h after treatment. Necropsy and histopathology were performed 24h after the last dose. The treatment with minoxidil induced myocardial necrosis, coronary arteriopathy and degeneration of renal tubules in animals treated with 150 mg/kg or 200 mg/kg. Myocardial necrosis associated with fibrosis in some animals was located mainly in the left and right ventricles (including papillary muscles), but also in the right atrium, left atrium and/or interventricular septum. Arteriopathy was observed in small coronary arteries of the right or left atrium. ECG and echocardiographic examinations showed that in animals treated with 150 mg/kg or 200 mg/kg, there were positive chronotropic and inotropic effects that compensated for the hypotensive effect of the drug and were considered to have played a key role in the pathogenesis of the cardiovascular lesions. The cardiotoxicity of minoxidil in marmosets was similar to that described in dogs, but occurred at much higher doses. In conclusion minoxidil produced cardiovascular toxicity in the marmoset, which was probably due to the marked changes in the cardiac function associated with exaggerated pharmacological effects of the compound. The marmosets were found to be less sensitive than dogs to the cardiotoxicity of minoxidil.

A model of orthostatic hypotension in the conscious monkey using lower body negative pressure.

INTRODUCTION: Methods most commonly used for detecting susceptibility to orthostatic hypotension in humans include head-up tilt and the application of lower body negative pressure (LBNP). The objective of this study was to evaluate the use of LBNP for detecting drug-induced changes in susceptibility to orthostatic hypotension in conscious monkeys (Macaca fascicularis). METHODS: Orthostatic responses were produced using an airtight chamber, which sealed around the stomach (umbilical area) and enclosed the lower body, to which were applied successive decrements of 10 mmHg chamber pressure every 5 min until the orthostatic response was observed. Cardiovascular measurements, involving arterial pressures, heart rate, and left ventricular pressures were recorded. The hypotensive agents prazosin and minoxidil were administered to evaluate the ability of the procedure to detect drug-induced changes in the susceptibility to orthostatic hypotension. RESULTS: A rapid decrease in systolic arterial pressure of >20 mmHg occurring within a 30 s time period was determined to be the best indicator of an orthostatic response. The application of LBNP produced an orthostatic response in all monkeys and on all occasions (100% response). The onset, rate and magnitude of the decrease in systolic blood pressure were also consistent for each monkey. Prazosin (>or=0.16 mg/kg, iv) produced an increase in the susceptibility to the orthostatic response, whereas minoxidil (10 mg/kg, po) had no effect. These results are consistent with previous findings in humans, where similar decreases in arterial pressures occur following the administration of prazosin and minoxidil, whereas increased susceptibility to orthostatic hypotension only occurs with prazosin. DISCUSSION: The results of this study demonstrate that the application of the LBNP is a reliable method for producing an orthostatic hypotensive response in conscious monkeys. In addition, the use of positive (prazosin) and negative (minoxidil) controls demonstrated that the use of LBNP is a valid method for evaluating the effect of drug treatment on susceptibility to orthostatic hypotension.

Use of M-mode and Doppler echocardiography to investigate the cardiotoxicity of minoxidil in beagle dogs.

Doppler and M-mode echocardiography (EC) were used to investigate the effects of minoxidil on the cardiac function of the dog and potentially to clarify the pathogenesis of cardiac lesions, in particular the necrotic lesion in the left ventricle and the haemorrhagic lesion in the right atrium. Groups of three dogs were treated with a single oral dose of 0.5 or 2 mg/kg minoxidil or control vehicle, and M-mode and Doppler parameters were recorded at different time points before as well as 1, 3 and 24 h after treatment. The treatment produced a number of changes in M-mode parameters that indicate an increase in left ventricle contractility, in particular, increases in the percentage of thickening of the left ventricle wall during systole and in ejection fraction, and decrease of systolic volume. There was also a decrease in diastolic volume, which indicates a decrease in filling of the left ventricle probably due to the tachycardia and subsequent decrease in inter-systolic time. Doppler EC showed an increase in the velocity of the aortic flow, which indicates an increase in cardiac contractility. There was also a mild increase in stroke volume, which together with the tachycardia resulted in a marked increase in cardiac output. Together, Doppler and M-mode recordings gave evidence of an increase in the contractility of the left ventricle. This change is consistent with the generally accepted mechanism for the development of the left ventricle lesion induced by minoxidil. Minoxidil also produced changes in atrio-ventricular flows. The velocity and/or acceleration of E- and A-waves of the mitral and tricuspid flows increased, and the E/A ratio decreased. The changes in the E-wave indicate a faster diastole of the ventricle probably to compensate for the decrease in inter-systolic time. The changes in A wave are characteristic of an increased amplitude and velocity of the atrial contraction. This latter change is much more marked for tricuspid than for mitral flow. For both flows the E/A ratio decreased, which indicates that the contraction of the atria plays an increased role in ventricle filling after minoxidil treatment. This stimulation of atrial contraction that we evaluate with Doppler EC may play a key role in the development of the atrial lesion produced by minoxidil. The fact that the change is more marked in the right than in the left atrium may explain why the lesion occurs only in the right atrium in dogs. This study showed, therefore, that Doppler EC associated with M-mode EC is a useful method for obtaining pertinent information on the pathogenesis of the left ventricle lesion induced by haemodynamic mechanisms. Moreover, Doppler EC allowed the assessment of changes in the function of the right atrium that may be involved in the development of the right atrial lesion.

[Effectivity versus toxicity of minoxidil as antiproliferative agent for lens epithelial cells. In vitro study]. / Efectividad versus toxicidad del minoxidil como agente antiproliferativo de células epiteliales de cristalino. Estudio in vitro.

PURPOSE: To evaluate the inhibitory effect of minoxidil on cultured proliferating lens epithelial cells (LECs) versus cytotoxic effect over corneal endothelial cells in culture, because minimum side effects over anterior chamber structures and particularly on corneal endothelium are required for successful therapy and prevention of posterior capsular opacification (PCO). METHODS: New Zealand Rabbit LECs and corneal endothelium were cultured in DMEM at 35 degrees C in 5% CO2 in multiwells during 7 days. Both types of cells were exposed to minoxidil (1, 2 and 4 mM) for 1 and 24 hours. Control group and balanced salt solution group were included. After seven days multiwells were processed for light microscopy study. Morphometric study of cellular population of LECs and corneal endothelium cells were done using a computed planimetry system. RESULTS: Dose-dependent effect on LECs proliferation was noted and non-confluent colonies of cells were observed on all treated groups. Morphologic changes in normal appearance of corneal endothelial cells after 1 hour of minoxidil treatment was observed and intracellular alterations were confirmed even with the lowest dose exposure. CONCLUSIONS: Although effectiveness of minoxidil suppressing in vitro LECs proliferation could be suggest as a useful therapeutic agent to prevent PCO, however the inhibitory effect of different concentrations on corneal endothelial cells conditioned its possible use on ocular surgery.

Arterial lesions induced by phosphodiesterase III (PDE III) inhibitors and DA(1) agonists.

Compounds that inhibit the low Km, cGMP-inhibitable form of phosphodiesterase (type III) and the DA(1) agonist, fenoldopam, are potent vasodilators that have been associated with segmental medial haemorrhagic necrosis in susceptible arterial beds following administration of suprapharmacological doses to dogs and/or rats. Morphological and haemodynamic investigative studies with PDE III inhibitors support the hypothesis that the arterial toxicity is the consequence of the vasodilator pharmacology of these compounds. Investigative data also suggest that similar mechanisms are involved in the pathogenesis of arterial lesions induced by fenoldopam and the K(+) channel opener, minoxidil.

Minoxidil-induced cardiac hypertrophy in guinea pigs.

To investigate whether during cardiac hypertrophy changes occur in contractile protein composition and in mechanical and energetic properties of the myocardium, contractile protein composition, isometric force and adenosine triphosphate (ATP) consumption were studied in control and hypertrophied guinea-pig hearts. Cardiac hypertrophy was induced by adding minoxidil (120 or 200 mg/l) to the drinking water. Protein analysis was performed by one-dimensional gel electrophoresis. The myosin heavy-chain (MHC) composition was determined in an enzyme-linked immunosorbent assay (ELISA). ATP consumption and force development were simultaneously measured during isometric contraction in chemically skinned trabeculae. Histochemical analysis of cross-sectional area of cardiomyocytes and interstitial space was performed on the left ventricular tissue of 200 mg/l minoxidil-treated and control guinea pigs. Minoxidil treatment (120 and 200 mg/l) significantly increased left ventricular dry weight normalized for body weight by 19 +/- 4 and 24 +/- 4%, respectively. No significant differences were found in the cellular cross-sectional area, while interstitial space was slightly decreased in minoxidil-treated hearts. In left ventricular trabeculae of 200 mg/l minoxidil-treated guinea pigs, ATPase activity was slightly less than in those of control guinea pigs, whereas force did not differ significantly. Calcium sensitivity of force and ATPase activity were not affected by minoxidil treatment. Gel electrophoresis revealed no difference in contractile protein composition, but a tendency towards a lower amount of alpha-MHC in the minoxidil-treated hearts was found in ELISA.

Minoxidil accelerates heart failure development in rats with ascending aortic constriction.

To test the ability of the heart to express characteristic geometric features of concentric and eccentric hypertrophy concurrently, constriction of the ascending aorta was performed in 4-week-old rats. Simultaneously, these rats were treated with an arteriolar dilator minoxidil. An examination 6 weeks after induction of the hemodynamic overload revealed no signs of congestion in systemic or pulmonary circulation in rats with aortic constriction or minoxidil-treated sham-operated rats. The magnitude of hemodynamic overload caused by aortic constriction or minoxidil treatment could be considered as equivalent, because the same enlargement of left ventricular pressure-volume area was necessary to compensate for either pressure or volume overload. Myocardial contractility decreased in rats with aortic constriction, and the compensation was achieved wholly by the marked concentric hypertrophy. Volume overload in minoxidil-treated rats was compensated partially by the eccentric hypertrophy and partially by the increased myocardial contractility. In contrast, increased lung weight and pleural effusion were found in all minoxidil-treated rats with aortic constriction. Unfavorable changes in left ventricular mass and geometry, relatively high chamber stiffness, and depressed ventricular and myocardial function were responsible for the massive pulmonary congestion.

Age dependence of the cardiac lesions induced by minoxidil in the rat.

To evaluate the age- and dose-dependence of the cardiotoxicity induced by minoxidil, histologic studies were made of the hearts of 3-, 6-, 15- and 24-month-old Sprague Dawley rats treated with either 10, 50 or 250 mg/kg of the drug p.o. daily for two consecutive days. The 10 mg/kg dose of minoxidil induced myocyte necrosis in each of the 24-month-old rats but only in one other animal (6-month-old). The 50 mg/kg dose produced necrosis in all the 15- and 24-month-old rats, but in only one of the other animals (6-month-old), while the 250 mg/kg dose induced necrosis in animals of all ages. Inflammation was present in all minoxidil-treated animals, but at each dose level it was most severe in the oldest rats. Interstitial hemorrhages were observed at all dose levels, but increased in frequency and severity with the dose of minoxidil, and at each dose level they were more severe in the oldest animals. Vascular lesions consisting of arteriolar damage and calcification were observed only in the 24-month-old animals. Thus, these data demonstrate that the cardiac lesions induced by minoxidil are more frequent and severe in older than in younger rats.

The pharmacologic basis of the cardiovascular toxicity of minoxidil in the dog.

Minoxidil (MNX), like several other vasoactive drugs, causes cardiovascular toxicity in dogs by undetermined mechanisms. We studied the mechanism of cardiovascular toxicity of MNX [an adenosine triphosphate (ATP)-sensitive potassium channel opener] by blocking its pharmacologic effects with glyburide (an ATP-sensitive potassium channel blocker) in groups of 5 female beagle dogs treated orally for 2 days with 1.0 mg/kg/day of MNX alone or with glyburide given in 5 or 6 divided doses of 300 mg/kg at 2 hr before and after each dose of MNX and at 3-6-hr intervals thereafter. A third group of 5 dogs received glyburide alone in the same dosing regimen as in the combination group. Mean arterial pressure (MAP), heart rate (HR), the pharmacokinetics of MNX, and gross and microscopic changes in the heart were evaluated. Glyburide did not influence the pharmacokinetics of MNX but prevented or markedly attenuated the MNX-induced cardiovascular lesions (right atrial hemorrhagic lesions, subendocardial necrosis, or coronary arteritis) occurred in dogs whose MNX-induced hemodynamic effects were effectively blocked by glyburide. In conclusion, the cardiovascular toxicity of MNX in dogs is not caused by a direct toxic effect of MNX on the heart but apparently is related to the exaggerated pharmacologic/profound hemodynamic effects it elicits in the dog.

Structural and functional consequences of minoxidil-induced cardiac hypertrophy.

Minoxidil, a potent arteriolar vasodilator, is used clinically as an antihypertensive agent, providing blood pressure control in patients who are resistant to conventional drug therapy. In spite of its antihypertensive effects, however, minoxidil treatment does not result in regression of cardiac hypertrophy. Laboratory studies have shown that minoxidil treatment actually causes cardiac enlargement when administered to normotensive animals. The mechanism of minoxidil-induced cardiac hypertrophy and its consequences for the myocardium have not been determined. Because cardiac hypertrophy is a significant independent risk factor for cardiovascular morbidity and mortality, it is important to understand this dissociation between blood pressure and cardiac enlargement and also to consider the possible impact of such findings on the clinical use of minoxidil. In the investigation presented here, we examined the structure and function of cardiac muscle from normotensive rats who developed myocardial hypertrophy after minoxidil treatment. Data demonstrate that minoxidil produces enlargement of the left ventricle, right ventricle and interventricular septum. The right ventricular enlargement produced by minoxidil treatment is due to an increase in myocyte cross-sectional area, a finding which may suggest pressure overload of the right ventricle. Left ventricular and septal enlargement in this model cannot be totally accounted for by an increase in myocyte cross-sectional area, suggesting that minoxidil causes enlargement by a mechanism other than pressure overload in these areas of the heart. Functionally, left ventricular papillary muscles from hearts with minoxidil-induced hypertrophy develop force which is equal to that developed by control muscles, but contract and relax more slowly than muscles from control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the arterial vasodilator minoxidil on cardiovascular structure and sympathetic activity in spontaneously hypertensive rats.

OBJECTIVE AND DESIGN: In spontaneously hypertensive rats (SHR) arterial vasodilators do not cause regression and might cause further progression of cardiac hypertrophy. To assess whether these effects extend to the vasculature, and to examine the possible mechanisms involved, cardiac and mesenteric arterial structure was evaluated with respect to changes in cardiac volume load and cardiac and arterial sympathetic activity during long-term (5- and 10-week) treatment of 16-week-old SHR with the arterial vasodilator minoxidil, alone or in combination with the diuretic hydrochlorothiazide. RESULTS: Despite causing a persistent decrease in blood pressure in SHR, minoxidil further increased left and right ventricular weights and left ventricular internal diameter. In combination with hydrochlorothiazide, minoxidil caused concentric, rather than eccentric, left ventricular hypertrophy. In the mesenteric arterial bed of SHR, minoxidil increased the lumen of the superior mesenteric artery, and prevented further increases in the medial area of the large and small mesenteric arteries. The increase in lumen size of the superior mesenteric artery by minoxidil was abolished when hydrochlorothiazide was added to the treatment. After 10 weeks' treatment with minoxidil, noradrenaline turnover rates were still significantly increased in the left ventricle but were decreased in the mesenteric arteries in the SHR. Minoxidil increased plasma and blood volumes, the increases being largely prevented by concomitant diuretic treatment. CONCLUSIONS: We conclude that there are regional differences in the response of the cardiovascular system to minoxidil in SHR. Some of these differences may be related to differences in regional sympathetic activity, whereas volume load appears to play a modulatory role.

Renin-angiotensin system and minoxidil-induced cardiac hypertrophy in rats.

Besides cardiac volume overload, cardiac sympathetic activity and the renin-angiotensin system (RAS) are activated by arterial vasodilators such as minoxidil. To evaluate the possible involvement of the RAS in the development of minoxidil-induced cardiac hypertrophy, we assessed in normotensive rats minoxidil-induced changes in cardiac and plasma renin activity (PRA) and the potential of chronic treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril and the nonpeptide angiotensin II receptor blocker losartan to prevent minoxidil-induced cardiac hypertrophy. PRA increased in parallel with the increase in cardiac filling pressures and development of cardiac hypertrophy, whereas the increase in cardiac renin activity was delayed as compared with these changes. Losartan did not decrease left ventricular end-diastolic pressure (LVEDP) but prevented the remodeling of the heart by minoxidil. In contrast, enalapril nearly normalized LVEDP but did not affect the hypertrophic response of the heart. The losartan data indicate that the RAS is involved in the minoxidil-induced cardiac hypertrophy either directly (e.g., by mediating the hypertrophic response of the heart to cardiac volume overload) or indirectly (e.g., by potentiating cardiac sympathetic activity). The ineffectiveness of enalapril has no obvious explanation but may possibly indicate ineffective blockade of angiotensin II formation in the heart in this model.

Cardiotoxicity of hydralazine and minoxidil in the rat. Influence of age.

In this study, the cardiotoxicity of isoproterenol, hydralazine and minoxidil was compared between young (1.5 months old) and mature (5 months old) rats. Both age classes were also compared for the effect of hydralazine on blood pressure and heart rate. For the 3 compounds, myocardial necrosis was observed and was more marked in mature than in young rats. The age-related increase in sensitivity to cardiotoxic effects which has already been described for isoproterenol, can therefore be extended to hydralazine and minoxidil. Hydralazine produced hypotension and reflex tachycardia. This latter effect appeared to have a longer duration in mature animals, which may be one of the explanation for their increased sensitivity to the cardiotoxic effect of the compound.

Pathogenesis of cardiovascular alterations in dogs treated with minoxidil.

Minoxidil and other potent vasodilators cause coronary arterial injury, right atrial hemorrhagic lesions, and subendocardial necrosis in dogs. This paper discusses the pathogenesis of coronary arterial and right atrial lesions associated with minoxidil in the dog. Acute coronary vascular injury characterized by segmental medial hemorrhage and necrosis and perivascular inflammation occurred only during the first few days of treatment, after which tolerance to further acute injury developed. At 30 d or more of treatment, coronary vascular injury was characterized by perivascular fibrosis rarely attended by medial distortion or hyperplasia and subintimal thickening, changes consistent with responses to previous injury. Right atrial hemorrhagic lesions, unlike coronary vascular injury, often became progressively more extensive with continued treatment. At 3 d, atrial hemorrhage and inflammation were confined to the subepicardium of the right atrium, evidently around affected subepicardial branches of the right coronary artery. At 30 d, fibrovascular proliferative right atrial lesions (granulation tissue with evidence of continual hemorrhage) extended from the epicardium to the myocardium, with eventual replacement of the atrial wall by mature connective tissue at 1 yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a beta-blocker (propranolol), or an alpha-blocker (dibenzylene), or by sympathetic neural activity suppression (surgical sympathectomy or constant carotid sinus nerve stimulation), suggesting that the sympathetic response to the pharmacologic activity of minoxidil was not responsible for the induction of the cardiovascular lesions. Minoxidil-related vascular lesions were confined to the most pharmacologically responsive segment of the arterial system, the coronary arteries, suggesting that medial injury may have been associated with tensile changes in the arterial wall.